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- PDB-3fh5: Leukotriene A4 Hydrolase complexed with inhibitor (2R)-2-[(4-benz... -

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Basic information

Entry
Database: PDB / ID: 3fh5
TitleLeukotriene A4 Hydrolase complexed with inhibitor (2R)-2-[(4-benzylphenoxy)methyl]pyrrolidine.
ComponentsLeukotriene A-4 hydrolase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / LTA4H / Leukotriene A4 / Leukotriene B4 Biosynthesis / Peptidase / Hydrolase-hydrolase inhibitor complex / Structure Based Drug Design / Leukotriene biosynthesis / Metal-binding / Metalloprotease / Multifunctional enzyme / Protease
Function / homology
Function and homology information


leukotriene-A4 hydrolase / leukotriene-A4 hydrolase activity / tripeptide aminopeptidase activity / tripeptide aminopeptidase / Biosynthesis of protectins / protein metabolic process / Biosynthesis of aspirin-triggered D-series resolvins / Biosynthesis of E-series 18(R)-resolvins / Biosynthesis of D-series resolvins / Biosynthesis of E-series 18(S)-resolvins ...leukotriene-A4 hydrolase / leukotriene-A4 hydrolase activity / tripeptide aminopeptidase activity / tripeptide aminopeptidase / Biosynthesis of protectins / protein metabolic process / Biosynthesis of aspirin-triggered D-series resolvins / Biosynthesis of E-series 18(R)-resolvins / Biosynthesis of D-series resolvins / Biosynthesis of E-series 18(S)-resolvins / Synthesis of Leukotrienes (LT) and Eoxins (EX) / epoxide hydrolase activity / leukotriene biosynthetic process / response to zinc ion / peptide catabolic process / type I pneumocyte differentiation / metalloaminopeptidase activity / aminopeptidase activity / response to peptide hormone / lipid metabolic process / tertiary granule lumen / peptidase activity / ficolin-1-rich granule lumen / Neutrophil degranulation / proteolysis / RNA binding / extracellular exosome / extracellular region / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal domain / Leukotriene A4 hydrolase/leucine aminopeptidase / Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal / Peptidase M1, LTA-4 hydrolase/aminopeptidase, C-terminal domain superfamily / : / Leukotriene A4 hydrolase, C-terminal / Leukotriene A4 hydrolase, C-terminal / Aminopeptidase, leukotriene A4 hydrolase-like / Zincin-like - #30 / Zincin-like ...Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal domain / Leukotriene A4 hydrolase/leucine aminopeptidase / Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal / Peptidase M1, LTA-4 hydrolase/aminopeptidase, C-terminal domain superfamily / : / Leukotriene A4 hydrolase, C-terminal / Leukotriene A4 hydrolase, C-terminal / Aminopeptidase, leukotriene A4 hydrolase-like / Zincin-like - #30 / Zincin-like / tricorn interacting facor f3 domain / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Aminopeptidase N-like , N-terminal domain / Peptidase family M1 domain / Peptidase M1 N-terminal domain / Aminopeptidase N-like , N-terminal domain superfamliy / Neutral Protease Domain 2 / Neutral Protease; domain 2 / Peptidase M4/M1, CTD superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Armadillo-type fold / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
(2R)-2-[(4-benzylphenoxy)methyl]pyrrolidine / ACETATE ION / IMIDAZOLE / YTTERBIUM (III) ION / Leukotriene A-4 hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.63 Å
AuthorsMamat, B. / Davies, D.R.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis.
Authors: Sandanayaka, V. / Mamat, B. / Mishra, R.K. / Winger, J. / Krohn, M. / Zhou, L.M. / Keyvan, M. / Enache, L. / Sullins, D. / Onua, E. / Zhang, J. / Halldorsdottir, G. / Sigthorsdottir, H. / ...Authors: Sandanayaka, V. / Mamat, B. / Mishra, R.K. / Winger, J. / Krohn, M. / Zhou, L.M. / Keyvan, M. / Enache, L. / Sullins, D. / Onua, E. / Zhang, J. / Halldorsdottir, G. / Sigthorsdottir, H. / Thorlaksdottir, A. / Sigthorsson, G. / Thorsteinnsdottir, M. / Davies, D.R. / Stewart, L.J. / Zembower, D.E. / Andresson, T. / Kiselyov, A.S. / Singh, J. / Gurney, M.E.
History
DepositionDec 8, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 5, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Nov 20, 2019Group: Derived calculations / Category: pdbx_struct_conn_angle / struct_conn
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Leukotriene A-4 hydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,3329
Polymers69,3641
Non-polymers9688
Water7,999444
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.401, 87.007, 99.847
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Leukotriene A-4 hydrolase / Leukotriene A(4) hydrolase / LTA-4 hydrolase


Mass: 69363.969 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LTA4H, LTA4 / Production host: Escherichia coli (E. coli) / References: UniProt: P09960, leukotriene-A4 hydrolase

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Non-polymers , 7 types, 452 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-YB / YTTERBIUM (III) ION


Mass: 173.040 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Yb
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H5N2
#6: Chemical ChemComp-24P / (2R)-2-[(4-benzylphenoxy)methyl]pyrrolidine


Mass: 267.365 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21NO
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 444 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.45 Å3/Da / Density % sol: 49.89 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 13% PEG 8000, 100 MM IMIDAZOLE PH 6.5, 100 MM SODIUM ACETATE, 5 MM YBCL3,, VAPOR DIFFUSION, SITTING DROP, temperature 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.63→50 Å / Num. obs: 84142 / % possible obs: 98.1 % / Redundancy: 5.2 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 18.4
Reflection shellResolution: 1.63→1.69 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.316 / % possible all: 94.3

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.5.0053refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1hs6

1hs6


Resolution: 1.63→50 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.936 / SU B: 1.458 / SU ML: 0.051 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.092 / ESU R Free: 0.089 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.208 4213 5 %RANDOM
Rwork0.183 ---
obs0.184 84096 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 15.06 Å2
Baniso -1Baniso -2Baniso -3
1--0.34 Å20 Å20 Å2
2---0.99 Å20 Å2
3---1.33 Å2
Refinement stepCycle: LAST / Resolution: 1.63→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4833 0 43 444 5320
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0225003
X-RAY DIFFRACTIONr_angle_refined_deg1.2321.9676795
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5755607
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.71924.338219
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.10415851
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1521523
X-RAY DIFFRACTIONr_chiral_restr0.0840.2755
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213767
X-RAY DIFFRACTIONr_mcbond_it0.5671.53039
X-RAY DIFFRACTIONr_mcangle_it1.11224932
X-RAY DIFFRACTIONr_scbond_it2.06831964
X-RAY DIFFRACTIONr_scangle_it3.3954.51862
LS refinement shellResolution: 1.63→1.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.259 289 -
Rwork0.222 5533 -
obs--92.44 %

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